Ginsenoside Rg1 promoted the wound healing in diabetic foot ulcers via miR-489-3p/Sirt1 axis.

PURPOSE: Diabetic foot ulcers (DFUs) are common complications of high severity for diabetes. Ginsenoside Rg1 (Rg1) has the potential for diabetes and cardiovascular diseases therapy. This research aimed at exploring the regulation of Rg1 on DFUs treatment and the underlying mechanism. METHODS: Human umbilical vein endothelial cells (HUVECs) incubated with high-glucose culture medium were established for induction of diabetes model. The MTT assay, Annexin V/PI assay and oxidative stress detection were carried out on high-glucose-induced HUVECs. Dual-luciferase reporter assay was performed to prove the interaction of miR-489-3p and Sirt1. DFUs model was established to determine the efficiency of Rg1 and miR-489-3p in wound closure of DFUs in vivo. RESULTS: Rg1 promoted cell proliferation, migration and angiogenesis, and reduced cell apoptosis in high-glucose-induced HUVECs. Knockdown of miR-489-3p alleviated the high-glucose-induced damage to HUVECs, while overexpression of miR-489-3p attenuated the protection effects of Rg1. Overexpression Sirt1 promoted wound healing in DFUs and Sirt1 was a direct target of miR-489-3p. In addition, animal experiments demonstrated that Rg1 promoted wound closure by regulating miR-489-3p/Sirt1 axis. CONCLUSIONS: Rg1 alleviated the DFUs by increasing Sirt1 expression via miR-489-3p downregulation and promoting activation of PI3K/AKT/eNOS signaling.

Associations between Nutrients and Foot Ulceration in Diabetes: A Systematic Review.

We reviewed the literature to evaluate potential associations between vitamins, nutrients, nutritional status or nutritional interventions and presence or healing of foot ulceration in diabetes. Embase, Medline, PubMed, and the Cochrane Library were searched for studies published prior to September 2020. We assessed eligible studies for the association between nutritional status or interventions and foot ulcers. Fifteen studies met the inclusion criteria and were included in this review. Overall, there is a correlation between poor nutritional status and the presence of foot ulceration or a delay in healing. However, there is not enough data to reach conclusions about whether the relationships are causal or only association. Further research is required to test whether any forms of nutritional supplementation improve foot ulcer healing.

Photobiomodulation: systematic review and meta-analysis of the most used parameters in the resolution diabetic foot ulcers.

The most common photobiomodulation parameters used to aid in the treatment of diabetic foot ulcers were investigated in this paper. The databases MEDLINE, LILACS, MEDCARIB, PAHO-IRIS, and WHOLIS were searched with the following descriptors: diabetic foot ulcers AND low-level laser therapy OR low-level therapy AND wound healing; this search was conducted from January of 2014 to December of 2019. Inclusion criteria were randomized clinical trials on humans. Exclusion criteria were systematic reviews, literature reviews, studies with animals, studies lacking photobiomodulation parameters, and studies with non-diabetic individuals. The Jadad scale was used in order to analyze the methodological quality of the matching papers. There were seventeen studies found on PubMed and four on LILACS. Among these, seven were selected, according to the inclusion and exclusion criteria. Two out of the seven matching studies obtained a high score, and five obtained a low score, on the Jadad scale. The studies settled on the use of 600-nm and 800-nm wavelength spectrum. Most of the analyzed papers on photobiomodulation on diabetic foot ulcers did not describe the detailed parameters in their methodology. None of the studies featured the maximum score with regard to the Jadad scale for methodological quality. The relations of energy versus wavelength and power versus wavelength were divergent among the parameters on the papers. Therefore, it is necessary to analyze the parameters for an optimized power value in order to improve the results of the treatment.

ARTERIAL INSUFFICIENCIES: Hyperbaric Oxygen Therapy for Selected Problem Wounds.

The use of hyperbaric oxygen (HBO2) for the treatment of selected problem wounds has focused almost entirely on the diabetic foot ulcer (DFU) in recent years. The prevalence of DFUs in today's patient population and the reimbursement available for the treatment of DFUs have given it priority status in discussions about problem wounds, but there are sound fundamental reasons why additional oxygen may have benefits in the treatment of non-DFU wounds.

Clinical study for external washing by traditional Chinese medicine in the treatment of multiple infectious wounds of diabetic foot: Study protocol clinical trial (SPIRIT compliant).

BACKGROUND: Diabetic foot (DF) is among the most serious complications of type 2 diabetes. DF infection (DFI) is a key factor in the deterioration and development of DF, so controlling infection plays an important role in the treatment of the disease. Traditional Chinese medicine foot bath has been widely used in China as a complementary and alternative therapy to improve circulation and infection control of DF. However, the existing evidence shows that its efficacy and safety are still insufficient. We report a study protocol about a multicenter, double-blind, randomized, placebo controlled trial which aims to make well-designed clinical trials to evaluate the efficacy and safety of herbal medicine foot bath decoction (FBD) and explore the mechanism of external washing of Chinese herbs in DFI. METHODS: This study is a multicenter, double-blind, randomized, placebo controlled clinical trial in which 60 eligible participants were randomly divided into an experimental group and control group at a 1:2 ratio. Both groups received the same basic treatment for DF disease, the experimental group used FBD and ordinary dressing changes, while half of the patients in the control group received placebo and ordinary dressings, and the other half received placebo and silver ion dressings. Patients in both groups will be evaluated weekly for efficacy during the intervention. The primary efficacy indicators include the types of wound pathogens, interleukin 6 and tumor necrosis factor α. Secondary efficacy indicators included blood glucose, blood lipids, wound area, lower extremity blood vessel diameter, blood flow speed, walking speed, walking distance, and traditional Chinese medicine syndrome scores. We will also conduct a safety evaluation of the drug at the end of the trial. DISCUSSION: This multicenter, double-blind, randomized, placebo clinical trial not only provides data on the efficacy and safety of FBD, but also provides a novel treatment strategy for clinicians and DF patients.

Practical Things You Should Know about Wound Healing and Vacuum-Assisted Closure Management.

LEARNING OBJECTIVES: After reading this article, the participant should be able to: 1. Understand the basics of negative-pressure wound therapy and practical uses of various vacuum-assisted closure dressings. 2. Understand the mechanisms of action of negative-pressure therapies and other important adjuncts, such as perfusion imaging. 3. Discuss the evidence for hyperbaric oxygen therapy in wound care. SUMMARY: Wound healing requires creating an environment that supports the healing process while decreasing inflammation and infection. Negative-pressure wound therapy has changed the way physicians manage acute and chronic wounds for more than 20 years. It contracts wound edges, removes exudate, including inflammatory and infectious material, and promotes angiogenesis and granulation tissue formation. These effects have been consistently demonstrated in multiple animal and human randomized controlled trials. Recent innovations that include instillation therapy and closed incision have further increased our arsenal against difficult-to-treat wounds and incisions at high risk of complications. Instillation of topical wound solutions allows physicians to cleanse the wound without return to the operating room, resulting in fewer debridements, shorter hospital stays, and faster time to wound closure. Other concepts have yielded negative-pressure therapy on top of closed surgical incisions, which holds incision edges together, reduces edema, promotes angiogenesis, and creates a barrier to protect incisions during the critical healing period, thereby reducing surgical-site complications, especially infection. Other practical adjuncts to the modern-day treatment of acute and chronic wounds include indocyanine green angiography, which allows real-time assessment of perfusion, and hyperbaric oxygen treatment, which has been suggested to augment healing in acute, chronic, specifically diabetic foot ulcers and radiation-related wounds.

Hyperbaric oxygen therapy for nonischemic diabetic ulcers: A systematic review.

Diabetic foot ulcers are a common complication of diabetes, which affects 25% of patients and may ultimately lead to amputation of affected limbs. Research suggests hyperbaric oxygen therapy improves healing of these ulcers. However, this has not been reflected in previous reviews, possibly because they did not differentiate between patients with and without peripheral arterial occlusive disease. Therefore, we performed a systematic review of published literature in the MEDLINE, Embase, and Cochrane CENTRAL databases on nonischemic diabetic foot ulcers with outcome measures including complete ulcer healing, amputation rate (major and minor), and mortality. Seven studies were included, of which two were randomized clinical trials. Two studies found no difference in major amputation rate, whereas one large retrospective study found 2% more major amputations in the hyperbaric oxygen group. However, this study did not correct for baseline differences. Two studies showed no significant difference in minor amputation rate. Five studies reporting on complete wound healing showed no significant differences. In conclusion, the current evidence suggests that hyperbaric oxygen therapy does not accelerate wound healing and does not prevent major or minor amputations in patients with a diabetic foot ulcer without peripheral arterial occlusive disease. Based on the available evidence, routine clinical use of this therapy cannot be recommended. However, the available research for this specific subgroup of patients is scarce, and physicians should counsel patients on expected risks and benefits. Additional research, focusing especially on patient selection criteria, is needed to better identify patients that might profit from this therapy modality.

Assessment of Mineral Pathophysiology in Patients with Diabetic Foot Ulcer.

Chronic non-healing diabetic foot ulcers (DFU) with a recurrence rate of over 50% in 3 years account for more than 1,08000 non-traumatic lower extremity amputations. Reports of altered mineral status and their role in pathogenesis of diabetes are well documented. However, little is known regarding their status and impact on severity of complications like foot ulcer. A hospital-based case control study was conducted in 64 subjects aged 40-60 years, attending the Podiatric and the Diabetes clinic of the institutional hospitals. Study subjects included were 32 diagnosed cases of type 2 diabetes having foot ulcers along with 32 age-matched diabetics without foot ulcer as controls. Fasting and post-prandial plasma glucose were estimated by glucose oxidase peroxidase method and HbA1c by high-performance liquid chromatography method. Serum zinc, magnesium and copper levels were estimated by colorimetric methods in semi-autoanalyser. Serum levels of zinc, copper and magnesium were significantly decreased in DFU cases as compared with diabetics without ulcers (p < 0.05). Correlation analysis revealed a significant inverse correlation of these minerals with all the glycaemic indices; the association being the strongest in case of zinc in both groups. The higher degree of mineral insufficiencies in the foot ulcer group of this study could be responsible for worsening the glycaemic control in diabetics leading to delayed healing of foot ulcers. The observed decrease of serum copper, magnesium and zinc levels in diabetics with foot ulcers appears to be proportionally related to the length of the diabetic disease. Thus, continuous monitoring and dietary supplementation of minerals in case of severe deficiencies might be beneficial in halting the progression of such complications.

Effects of a topical botanically-enriched salve on cutaneous oxygenation.

OBJECTIVE: There is a medical need to evaluate new treatments that may improve wound healing. This study aimed to determine if Original Healing Salve (OHS, Puremedy, Inc.) a topical, botanically-enriched salve (BES), changes distal leg tissue oxygenation in people with type 2 diabetes. METHOD: A randomised, controlled, crossover, double-blinded clinical trial comparing changes in cutaneous oxygen delivery (mean TcPO2) on multiple sites of the lower extremity following application of a botanically-enriched topical salve, as compared with application of the salve's base in patients with type 2 diabetes. Subjects were recruited from the general population as a convenience sample. RESULTS: A total of 16 participants were recruited. Analysis of the primary outcome demonstrated no statistically significant difference in TcPO2 at 30 minutes postapplication when comparing the BES to the base salve (BS) on the leg (-0.39±8.54mmHg; p=0.86). Analyses of secondary outcomes at 30 minutes postapplication indicated that mean TcPO2 was significantly higher than preapplication levels among subjects receiving both the BES (3.70±6.62mmHg; p=0.04) and BS on the leg (4.08±5.21mmHg; p=0.007). On the foot, mean TcPO2 at 30 minutes postapplication was higher in the BES compared with the BS, this difference was not significant (0.98±8.59mmHg; p=0.66). Mean TcPO2 was higher than preapplication levels among subjects receiving both the BES (1.21±7.70mmHg; p=0.54) and BS on the foot (2.19±7.27mmHg; p=0.25). These differences were non-significant. CONCLUSION: These findings support consideration of topical treatments containing botanical ingredients to increase cutaneous oxygen delivery in the lower extremity in patients with type 2 diabetes.

Regeneration of Diabetic Foot Ulcers Based on Therapy with Red LED Light and a Natural Latex Biomembrane.

This study analyzes the effects of the Rapha® system, which employs red light therapy (RLT) and a natural latex biomembrane in the healing of neuropathic ulcers associated with the diabetic foot. We conducted a randomized, controlled, blinded clinical trial with 15 participants that were divided into three groups (GI, GII and GIII): (i) Rapha® system application by the participant and a health professional at home, with clinical status evaluation every 2 weeks at the hospital (GI); (ii) standard protocol used in Brazil, performed by a health professional at the hospital (GII; control); and (iii) the Rapha® system applied by the participant at home and clinical status evaluation every 2 weeks at the hospital (GIII). We used image processing techniques on photographic recordings of the lesions, and several statistical tests were used to analyze the data, allowing for the comparison of the average results for all groups. The average healing rates of GI, GII, and GIII were 77.0, 51.4, and 80%, respectively. The granulation tissue evaluation indicated a higher efficacy in the tissue repair of lesions treated with the Rapha® system. In conclusion, the Rapha® system proved to be an effective healing system, even when self-applied at the patient's home.

Lower Limb Nonhealing Ulcers Associated With Chronic Diabetes: A Case Series.

INTRODUCTION: Chronic, nonhealing skin ulcers of the lower limbs associated with diabetes pose a clinical challenge as their treatment requires more sophisticated and delicate approaches than in patients without diabetes. OBJECTIVE: Herein, the authors demonstrate and discuss the implementation of their use of topical traditional Chinese medicines in several sample cases of lower limb nonhealing ulcers in patients with diabetes. MATERIALS AND METHODS: A series of diabetic ulcer cases were treated with various approaches. First, the approach employed with each patient was determined based on ulcer location, depth, inflammatory extent, and local circulation. Next, an exploratory incision was performed to evaluate eschar condition. Finally, the therapy applied was modified depending on specific case characteristics. RESULTS: The primary therapeutic approaches employed were: (1) selective partial ablation, including fenestration and encroachment; (2) debridement, which avoids secondary injury when local circulation is good; and (3) the turning-over method, in which necrotic tissue is cleaned down to the basal layer via application of a topical Chinese medicine that reduces inflammation and promotes chronic ulcer healing. CONCLUSIONS: These therapeutic approaches alleviated local inflammatory damage and adverse systemic reactions, which is an important basis for further treatment (eg, anti-infection treatment, blood glucose reduction, blood pressure control, organ function improvement, circulation promotion, and nutritional support).

Herbal medicine foot bath for the treatment of diabetic peripheral neuropathy: protocol for a randomized, double-blind and controlled trial.

BACKGROUND: As a common complication of diabetes, the incidence of diabetic peripheral neuropathy (DPN) is 60-70% worldwide. DPN is a major risk factor for diabetic foot, which may lead to foot ulceration and even amputation. The treatment of DPN remains challenging. Our preliminary study demonstrated that the external application of Tangbi Waixi (TW) decoction to the lower extremities relieved clinical symptoms and improved nerve conduction velocity in DPN patients. The aim of this study was to verify the efficacy of TW among DPN patients and evaluate the herb mixture's safety using rigorous methodological designs. METHODS/DESIGN: This study is a multicenter, double-blind, randomized controlled trial. A total of 640 DPN patients will be recruited and randomized to receive a foot bath with either the TW decoction or control drug. Participants will be assessed at baseline and 12 and 24 weeks after treatment. The primary outcome was the change of the Toronto Clinical Scoring System (TCSS). Secondary outcomes were nerve conduction velocity, blood glucose, blood lipids, serum inflammatory cytokines, and the European Quality of Life Five-Dimension Scale (EQ-5D) and TCM symptom scores. DISCUSSION: This multicenter, prospective, randomized clinical trial will provide valuable data regarding the efficacy and safety of foot bath treatment with TW decoction. Positive results would provide a novel treatment regimen for DPN patients. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-IOR-16009331 . Registered on 8 October 2016.

Chinese medicine ulcer oil promotes the healing of diabetic foot ulcers.

Objective This study aimed to investigate the mechanism by which Chinese herbal medicine ulcer oil (UO) accelerates ulcer healing in a diabetic ulcer rat model. Methods Sprague Dawley rats were allocated at random into four groups: a control group, a positive control group (PC), a UO treatment group and an ethacridine lactate solution treatment group. Subcutaneous tissue was surgically removed from the rats on days 3, 7 and 14. The levels of protein phosphotyrosine phosphatase 1B (PTP1B), vascular endothelial growth factor (VEGF), platelet-derived growth factor (PDGF) and advanced glycation end products (AGEs) were detected using western blot analysis. Results PTP1B protein expression was significantly lower in the UO group compared with the PC group. VEGF protein expression was significantly higher in the UO group than in the control group on day 3. PDGF protein expression in the UO group was significantly higher than in the PC group on day 3. AGE expression was significantly lower in the UO group than in the PC group. Conclusions UO may downregulate PTP1B and AGEs and upregulate VEGF and PDGF, which may contribute to the inhibition of the inflammatory response and promote the healing of diabetic foot ulcers.

Spectral analysis of the blood flow in the foot microvascular bed during thermal testing in patients with diabetes mellitus.

Timely diagnostics of microcirculatory system abnormalities, which are the most severe diabetic complications, is one of the major problems facing modern health care. Functional abnormalities manifest themselves earlier than the structural ones, and therefore their assessment is the issue of primary importance. In this study Laser Doppler flowmetry, a noninvasive technique for the cutaneous blood flow monitoring, was utilized together with local temperature tests and wavelet analysis. The study of the blood flow in the microvascular bed of toes was carried out in the control group of 40 healthy subjects and in two groups of 17 type 1 and 23 type 2 diabetic patients. The local temperature tests demonstrated that the diabetic patients have impaired vasodilation in response to local heating. The tendency for impaired low frequency pulsations of the blood flow associated with endothelial and neurogenic activities in both diabetes groups was observed. Local thermal tests induced variations in perfusion and its spectral characteristics, which were different in the groups under study. In our opinion, the obtained preliminary results can be a basis for further research and provide a deeper understanding of pathological processes that drive microvascular abnormalities caused by diabetes mellitus.

Computerized planimetry evaluation of hyperbaric oxygen therapy in the treatment of diabetic foot.

BACKGROUND: Diabetic foot ulcer is one of the major complications of diabetes mellitus in adults. OBJECTIVES: The aim of the study was to conduct a planimetry evaluation of the effectiveness of hyperbaric oxygen therapy (HBOT) in the treatment of patients with vascular disorders caused by diabetic foot. MATERIAL AND METHODS: The study included 94 patients, 30 females (32%) and 64 males (68%), aged 33-76 years, with diabetes lasting 1.5-32 years, who underwent HBOT due to diabetic foot. All patients from that group underwent vascular procedures prior to HBOT. In qualifying patients for hyperbaric oxygen therapy, transcutaneous oximetry method was applied (30-60 exposures in hyperbaric oxygen at pressure of 2.5 ATA). Progress in wound healing was evaluated by computerized planimetry system IRIS 4. RESULTS: In 26 patients the wounds were completely closed and in 37 patients the topical state was significantly improved - the wound surface decreased by 34% in average. During the treatment, in 11 patients amputation of fingers and metatarsal necrotic bones was performed, while in 9 patients amputation was prevented. CONCLUSIONS: A planimetry evaluation showed that the application of HBOT in the treatment of diabetic foot enhances foot ulcer healing, reduces tissue damage, contributes to the reduction of complications related to soft tissue and bone infections.

The use of indocyanine green fluorescence angiography to assess perfusion of chronic wounds undergoing hyperbaric oxygen therapy.

OBJECTIVE: The purpose of this study is to determine the utility of using indocyanine green fluorescence angiography (IGFA) in assessing perfusion of chronic wounds after hyperbaric oxygen (HBO2) therapy. METHODS: From May 2016 to January 2018, 26 patients underwent both HBO2 and IGFA. A near-infrared charge-coupled camera measured the flow of intravenous indocyanine green into the wound. IGFA was done pre-HBO2, after approximately 10 HBO2 sessions, and upon completion of HBO2. The ingress rate at baseline, mid-therapy and post-HBO2 values were compared using descriptive statistics. RESULTS: A total of 26 chronic wounds were identified. Baseline median ingress rate was 0.90 units/second (IQR: 0.28 to 6.10). Median ingress rate after approximately of 10 HBO2 sessions was 2.45 units/sec (IQR: 0.48 to 6.35). Six of 11 patients, however, exhibited a decrease in ingress rate from baseline to mid-therapy. Finally, median ingress rate post-HBO2 was 3.70 units/second (IQR: 0.30 to 9.90). Median increase in ingress and rate from baseline to mid-HBO2 treatment 0.30 units/second (IQR: -0.25 to 3.10) and from mid- to post-HBO2 was -0.40 units/second (IQR: -1.50 to 2.60). CONCLUSIONS: This preliminary study shows capability of IGFA to detect changes in blood flow to wounds following HBO2 therapy. Results support the use of IGFA to evaluate the changes in perfusion of patients undergoing HBO2 for chronic wounds. A larger sample size may help clarify the benefit of IGFA to predict potential for wound healing.

Micronutrients and Natural Compounds Status and Their Effects on Wound Healing in the Diabetic Foot Ulcer.

The diabetic foot ulcer (DFU) is an invariably common complication of diabetes mellitus, it is also a significant cause of amputation as well as extended hospitalization. As most patients with DFU suffer from malnutrition, which has been related to improper metabolic micronutrients status, alterations can affect impaired wound healing process. Micronutrients and herbal remedies applications present a wide range of health advantages to patients with DFU. The purpose of this review is to provide current evidence on the potential effect of dietary supplementations such as vitamins A, C, D, E, magnesium, zinc, copper, iron, boron, and such naturally occurring compounds as Aloe vera, Naringin, and Radix Astragali (RA) and Radix Rehmanniae (RR) in the administration of lower extremity wounds, especially in DFU, and to present some insights for applications in the treatment of DFU patients in the future.